ABSTRACT
In the previous article we have reported that 3,4-dihydroquinazoline 1 is a potent and selective T-type calcium channel blocker that exhibited strong anti-cancer activity in vitro. Compound 1·2HCl was further in vivo evaluated against A549 xenograft in BALB/c nude mice, which exhibited 49% tumor-weight inhibition through intravenous administration of 2 mg/kg of body weight and was more potent than doxorubicin. Moreover, compound 1·2HCl has an oral bioavailability of 98% with LD(50) values of 693 mg/kg (p.o. route) and 40.0 mg/kg (i.v. route) of body weight. In addition, its efficient scale-up synthetic method was developed.
Subject(s)
Antineoplastic Agents/pharmacology , Quinazolines/pharmacology , Animals , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Lethal Dose 50 , Mice , Mice, Inbred BALB C , Mice, Nude , Transplantation, HeterologousABSTRACT
First total synthesis of methylgerambullone (MGB, 1) isolated from Glycosmis angustifolia was completed via a convergent route. The effect of MGB on the contractile responses of the isolated guinea-pig ileum induced by acetylcholine was investigated. As a result, it showed a potent relaxation rate (78.66+/-4.30% at 100mg/L) in a concentration-dependent manner on longitudinal smooth muscle contraction of isolated guinea-pig ileum induced by 1microM acetylcholine.
Subject(s)
Acrylamides/chemical synthesis , Biological Products/chemical synthesis , Sulfones/chemical synthesis , Acetylcholine/pharmacology , Acrylamides/chemistry , Acrylamides/pharmacology , Animals , Biological Products/chemistry , Biological Products/pharmacology , Guinea Pigs , Ilium/drug effects , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects , Rutaceae/chemistry , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
In order to further clarify the role of T-type Ca(2+) channels in cell proliferation, we have measured the growth inhibition of human cancer cells by using our potent T-type Ca(2+) channel blockers. As a result, KYS05090, a most potent T-type Ca(2+) channel blocker, was found to be as potent as doxorubicin against some human cancer cells without acute toxicity. Therefore, this letter provides the biological results that T-type calcium channel is important in regulating the important cellular phenotype transition leading to cell proliferation, and thus novel T-type Ca(2+) channel blocker presents new prospects for cancer treatment.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/pharmacology , Calcium Channels, T-Type/chemistry , Drug Screening Assays, Antitumor , Quinazolines/pharmacology , Animals , Calcium Channels, T-Type/metabolism , Cell Line, Tumor , Cell Proliferation , Chemistry, Pharmaceutical/methods , Doxorubicin/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Quinazolines/chemical synthesisABSTRACT
In the chiral Co(III)(salen)-catalysed HKR of racemic epoxides, in the presence of ionic liquids, Co(II)(salen) complex is oxidised without acetic acid to catalytically active Co(III)(salen) complex during reaction and, moreover, this oxidation state is stabilised against reduction to Co(II) complex which enables the reuse of the recovered catalyst for consecutive reactions without extra reoxidation.
